One-Pot Approach for the Synthesis of trans-Cyclopropyl ... · compounds methyl diazoacetate and...
Transcript of One-Pot Approach for the Synthesis of trans-Cyclopropyl ... · compounds methyl diazoacetate and...
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SUPPORTING INFORMATION ________
One-Pot Approach for the Synthesis of trans-Cyclopropyl Compounds from Aldehydes. Application to the Synthesis of GPR40 Receptor
Agonists
Michaël Davi and Hélène Lebel*
Département de Chimie, Université de Montréal, 2900 Boul. Edouard Montpetit, Montréal, Québec, Canada H3T 1J4 Email: [email protected]
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GENERAL INFORMATION Unless otherwise noted, all non-aqueous reactions were run under an inert atmosphere (argon) with rigid exclusion of moisture from reagents and glassware using standard techniques for manipulating air-sensitive compounds.1 All glassware was stored in the oven and/or was flame dried prior to use under an inert atmosphere of gas. The solvents were dried using standard methods prior to use. Analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica gel (Merck 60 F254). Visualization of the developed chromatogram was performed by UV absorbance, aqueous cerium molybdate, ethanolic phosphomolybdic acid, iodine, or aqueous potassium permanganate. Flash column chromatography was performed using 230-400 mesh silica (EM Science or Silicycle) of the indicated solvent system according to standard technique.2 Melting points were obtained on a Buchi melting point apparatus and are uncorrected. Infrared spectra were taken on a Perkin Elmer Spectrum One FTIR and are reported in reciprocal centimeters (cm-1). Only the most important and relevant frequencies are reported. Nuclear magnetic resonance spectra (1H, 13C, DEPT 135, COSY, HMQC, NOESY) were recorded either on a Bruker AV 300, AMX 300, AV 400 or ARX 400 spectrometer (300, 300, 400 et 400 MHz respectively) in deuterochloroform, unless otherwise noted. Chemical shifts for 1H NMR spectra are recorded in parts per million (ppm) on the δ scale relative to an internal standard of residual solvent (chloroform, δ7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet and br = broad), coupling constant in Hz, integration, and assignment. Chemical shifts for 13C NMR spectra are recorded in parts per million from tetramethylsilane using the central peak of deuterochloroform (77.00 ppm) as the internal standard. All spectra were obtained with complete proton decoupling. When ambiguous, proton and carbon assignments were established using COSY, HMQC and DEPT experiments. High resolution mass spectra were performed by the Centre régional de spectroscopie de masse de l'Université de Montréal. Combustion analyses were performed by the Laboratoire d'analyse élémentaire de l'Université de Montréal. Copper(I) iodide CuI was purchased from Strem. The commercially available aldehydes were purified using standard methods prior to use. Triphenylphosphine was received from Aldrich Chemical Co and used without further purification. CAUTION!!! Diazo compounds are toxic and potentially explosive. They should be stored in refrigerator and handled with caution in a fume hood. Ethyl diazoacetate is commercially available from Aldrich, but was prepared from ethyl glycinate hydrochloride according to the literature.3 Diazomethane was prepared as a solution in dichloromethane (C = 0.30 to 0.50M).4 Other diazo compounds methyl diazoacetate and tert-butyldiazoacetate,5 diazoacetophenone,6 N,N-dimethyl diazoacetamide and N-methoxy-N-methyl diazoacetamide,7 dimethyl (diazomethyl)phosphonate8 were prepared following literature procedure.
1 Shriver, D. F.; Drezdzon, M. A. The manipulation of air-sensitive compounds; 2nd Edition ed.; Wiley: New York, 1986. 2 Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. 3 Searle N. E. Org. Synth. Coll. Vol. IV, 1963, 424. 4 de Boer T. J.; Backer, H. J. Org. Synth. Coll. Vol. IV, 1963, 250. 5 Regitz, M.; Hocker, J.; Liedhegener A. Org. Synth. Coll. Vol. V, 1973, 179. 6 Bridson, J.N.; Hooz J. Org. Synth. Coll. Vol. VI, 1988, 386. 7 Bartlett, P.A.; Carruthers, N.I.; Winter, B. M.; Long, K.P. J. Org. Chem. 1982, 47, 1284-91. 8 Ohira, S. Synth. Commun. 1989, 19, 561-564.
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GENERAL PROCEDURES Method A: Catalytic one-pot process in dichloromethane. CuI (10 mg, 0.050 mmol) and triphenylphosphine (262 mg, 1.00 mmol) were placed in a vessel which was backfilled with argon. Dichloromethane (4.0 mL) was added and the resulting solution was stirred for 5 minutes until the solution became clear. The aldehyde (1.00 mmol) was then added and the mixture was heated under reflux. After 5 minutes, ethyl diazoacetate (2.00 mmol) was added in one portion and the reaction was stirred until the reaction reached completion as gauged by GC, 1H NMR or TLC analysis. The mixture was cooled first to rt, then to -78 °C. Pd2(dba)3 (5 mg, 0.005 mmol) was added and a freshly prepared solution of diazomethane was slowly added (about 0.2 mL/min) until the reaction was completed. The conversion of the reaction was monitored either by NMR 1H or by GC/MS. The solvent was removed under reduced pressure and the crude cyclopropane was purified by flash chromatography on silica gel. Method B: Catalytic one-pot process in toluene. CuI (10 mg, 0.050 mmol) and triphenylphosphine (262 mg, 1.00 mmol) were placed in a vessel which was backfilled with argon. Toluene (4.0 mL) was added and the resulting solution was stirred for 5 minutes until the solution became clear. The aldehyde (1.00 mmol) was then added and the mixture was heated at 80 °C. After 5 minutes, ethyl diazoacetate (2.00 mmol) was added in one portion and the reaction was stirred until the reaction reached completion as gauged by GC, 1H NMR or TLC analysis. The mixture was cooled first to rt then to -78 °C. Pd(OAc)2 (2 mg, 0.01 mmol) was added and a freshly prepared solution of diazomethane was slowly added (about 0.2 mL/min) until the reaction was completed. The conversion of the reaction was monitored either by NMR 1H or by GC/MS. The solvent was removed under reduced pressure and the crude cyclopropane was purified by flash chromatography on silica gel. Method C: Catalytic one-pot process in dichloroethane. CuI (10 mg, 0.050 mmol) and triphenylphosphine (262 mg, 1.00 mmol) were placed in a vessel which was backfilled with argon. Dichloroethane (4 mL) was added and the resulting solution was stirred for 5 minutes until the solution became clear. The aldehyde (1.00 mmol) was then added and the mixture is heated at 80 °C. After 5 minutes, ethyl diazoacetate (2.00 mmol) was added in one portion and the reaction was stirred until the reaction reached completion as gauged by GC, 1H NMR or TLC analysis. The mixture was first to rt, then to -78 °C. Pd2(dba)3 (5 mg, 0.005 mmol) was added and a freshly prepared solution of diazomethane was slowly added (about 0.2 mL/min) until the reaction was completed. The conversion of the reaction was monitored either by NMR 1H or by GC/MS. The solvent was removed under reduced pressure and the crude cyclopropane was purified by flash chromatography on silica gel. CHARACTERIZATION OF PRODUCTS
Ph O PhCO2Et
1 (1R*,2R*)-Ethyl 2-phenylcyclopropanecarboxylate (1).9 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 1 (161 mg, 85%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.24 (10% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.30-7.17 (M, 3H), 7.11-7.09 (M, 2H), 4.17 (q, J = 7 Hz, 2H), 2.55-2.48 (m, 1H), 1.93-1.87 (m, 1H), 1.63-1.57 (m, 1H), 1.34-1.27 (m, 1H), 1.28 (t, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.3,
9 Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 8179 - 8184.
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140.0, 128.4, 126.4, 126.1, 60.6, 26.1, 24.1, 17.0, 14.2. IR (neat) 3060, 1662, 1600, 1283, 1223, 1012 cm-1. (1R*,2R*)-Ethyl 2-phenylcyclopropanecarboxylate (1). The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure B using 6.00 mmol of diazomethane. The desired cyclopropane 1 (131 mg, 69%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). (1R*,2R*)-Ethyl 2-phenylcyclopropanecarboxylate (1). The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure C using 6.00 mmol of diazomethane. The desired cyclopropane 1 (146 mg, 77%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes).
OCO2Et
2
CO2Me CO2Me Methyl 2-((1R*,2R*)-2-(ethoxycarbonyl)cyclopropyl)benzoate (2). The title compound was prepared from methyl 2-formylbenzoate10 (164 mg, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 2 (221 mg, 89%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.20 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8, 1 Hz, 1H), 7.44-7.40 (m, 1H), 7.30-7.26 (m, 1H), 7.13 (d, J = 8 Hz, 1H), 4.20 (q, J = 7 Hz, 2H), 3.88 (s, 3H), 3.14-3.09 (m, 1H), 1.78-1.73 (m, 1H), 1.63-1.58 (m, 1H), 1.36-1.31 (m, 1H), 1.30 (t, J = 7 Hz, 3H) ; 13C NMR (75 MHz, CDCl3) δ 173.5, 167.9, 140.5, 131.9, 131.4, 130.5, 127.2, 126.6, 60.5, 52.1, 25.4, 23.3, 15.6, 14.3; IR (neat) 2955, 1726, 1451, 1295, 1260, 1184 cm-1; HRMS (FAB) calcd for C14H17O4 [M+H]+
: 249.1121. Found 249.1120.
OCO2Et
3
Cl Cl (1R*,2R*)-Ethyl 2-(2-chlorophenyl)cyclopropanecarboxylate (3).11 The title compound was prepared from 2-chlorobenzaldehyde (113 µL, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropane 3 (157 mg, 70%) was obtained as a light yellow oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.25 (10% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.38-7.35 (m, 1H), 7.19-7.15 (m, 2H), 7.02-6.99 (m, 1H), 4.20 (q, J = 7 Hz, 2H), 2.78-2.71 (m, 1H), 1.84-1.78 (m, 1H), 1.65-1.59 (m, 1H), 1.35-1.28 (m, 1H), 1.29 (t, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.2, 137.4, 135.6, 129.3, 127.8, 127.0, 126.7, 60.7, 24.2, 22.9, 15.5, 14.2; IR (neat) 2981, 1726, 1445, 1408, 1326, 1182 cm-1.
OCO2Et
4
Br Br (1R*,2R*)-Ethyl 2-(2-bromophenyl)cyclopropanecarboxylate (4). The title compound was prepared from 2-bromobenzaldehyde (117 µL, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropane 4 (180 mg, 67%) was obtained as a light yellow oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.27 (10% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.56 (dd, J = 8, 1 Hz, 1H), 7.26-7.20 (m, 1H), 7.11-7.00 (m, 2H), 4.21 (q, J = 7 Hz, 2H), 2.74-2.67 (m, 1H), 1.82-1.76 (m, 1H), 1.65-1.59 (m, 1H), 1.36-1.28 (m, 1H), 1.29 (t, J = 7 Hz, 3H) ; 13C NMR (75 MHz, CDCl3) δ 173.2, 139.0, 132.5, 128.1, 127.4, 127.3, 126.2, 60.7, 26.9, 23.1, 15.6,
10 This compound was prepared from 2-carboxybenzaldehyde: Ye, B.-H.; Naruta, Y. Tetrahedron, 2003, 59, 3593-3601. 11 Kaiser, C.; Lester, B. M.; Zirkle, C. L.; Burger, A.; Davis, C. S.; Delia, T. J.; Zirngibl, L. J Med. Chem. 1962, 5, 1243-65.
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14.3. IR (neat) 2980, 1725, 1444, 1407, 1324, 1181 cm-1 ; HRMS (FAB) calcd for C12H14BrO2 [M+H]+
: 269.0171. Found 269.0175.
O
CO2Et
5
MeO MeO
(1R*,2R*)-Ethyl 2-(3-methoxyphenyl)cyclopropanecarboxylate (5).12 The title compound was prepared from m-anisaldehyde (122 µL, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropane 5 (202 mg, 92%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.46 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.64 (s, 1H), 4.16 (q, J = 7 Hz, 2H), 3.79 (s, 3H), 2.51-2.46 (m, 1H), 1.92-1.87 (m, 1H), 1.61-1.56 (m, 1H), 1.32-1.27 (m, 1H), 1.27 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3, 159.6, 141.7, 129.4, 118.4, 112.0, 111.6, 60.7, 55.1, 26.1, 24.1, 17.0, 14.2; IR (neat) 2980, 2835, 1722, 1603, 1407, 1181 cm-1; HRMS (FAB) calcd for C13H17O3 [M+H]+
: 221.1168. Found 221.1172.
O
CO2Et
6
(1R*,2R*)-Ethyl 2-p-tolylcyclopropanecarboxylate (6).9 The title compound was prepared from p-tolualdehyde (118 µL, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 6 (163 mg, 80%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.18 (5% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8 Hz, 2H), 6.99 (d, J = 8 Hz, 2H), 4.16 (q, J = 7 Hz, 2H), 2.52-2.45 (m, 1H), 2.31 (s, 3H), 1.89-1.83 (m, 1H), 1.60-1.53 (m, 1H), 1.31-1.14 (m, 1H), 1.27 (t, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 137.0, 136.0, 129.1, 126.0, 60.6, 25.9, 24.0, 20.9, 16.9, 14.2; IR (neat) 2981, 1725, 1405, 1331, 1182 cm-1.
O
CO2Et
7
Cl Cl (1R*,2R*)-Ethyl 2-(4-chlorophenyl)cyclopropanecarboxylate (7).13 The title compound was prepared from 4-chlorobenzaldehyde (140 mg, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 7 (169 mg, 75%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.32 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 4.17 (q, J = 7 Hz, 2H), 2.50-2.45 (m, 1H), 1.88-1.83 (m, 1H), 1.62-1.57 (m, 1H), 1.29-1.24 (m, 1H), 1.27 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 138.6, 132.1, 128.5, 127.5, 60.7, 25.4, 24.1, 17.0, 14.2; IR (neat) 2981, 1722, 1496, 1328, 1185 cm-1.
O
CO2Et
8
Br Br (1R*,2R*)-Ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (8).12 The title compound was prepared from 4-bromobenzaldehyde (185 mg, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 8 (193 mg, 72%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.35 (10% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.39 (d, J = 8 Hz, 2H), 6.96 (d, J = 8 Hz, 2H), 4.16 (q, J = 7 Hz, 2H), 2.50-2.43 (m, 1H),
12 Hixson, S. S.; Franke, L. A.; Gere, J. A.; Xing, Y. D. J. Am. Chem. Soc. 1988, 110, 3601-10. 13 Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Adv. Synth. Catal. 2001, 343, 79-88.
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1.89-1.83 (m, 1H), 1.63-1.56 (m, 1H), 1.29-1.23 (m, 1H), 1.27 (t, J = 7Hz, 3H) ; 13C NMR (75 MHz, CDCl3) δ 173.1, 139.1, 131.4, 127.8, 120.1, 60.8, 25.5, 24.1, 17.0, 14.2; IR (neat) 2984, 1720, 1495, 1408, 1328, 1183 cm-1.
O
CO2Et
9
MeO MeO (1R*,2R*)-Ethyl 2-(4-methoxyphenyl)cyclopropanecarboxylate (9).9 The title compound was prepared from p-anisaldehyde (121 µL, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 9 (168 mg, 76%) was obtained as a light yellow solid after flash chromatography (10% EtOAc/Hexanes). Rf 0.38 (20% EtOAc/hexanes). M.p. 83 °C (litt. 85 °C).14 1H NMR (300 MHz, CDCl3) δ 7.03 (d, J = 8 Hz, 2H), 6.82 (d, J = 8 Hz, 2H), 4.16 (q, J = 7 Hz, 2H), 3.78 (s, 3H), 2.51-2.44 (m, 1H), 1.85-1.79 (m, 1H), 1.58-1.52 (m, 1H), 1.28-1.22 (m, 1H), 1.27 (t, J = 7Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 158.2, 132.0, 127.3, 113.8, 60.6, 55.2, 25.6, 23.8, 16.7, 14.2. IR (neat) 2982, 1721, 1606, 1408, 1180 cm-1.
O
CO2Et
10
Me2N Me2N (1R*,2R*)-Ethyl 2-(4-(dimethylamino)phenyl)cyclopropanecarboxylate (10). The title compound was prepared from 4-dimethylaminobenzaldehyde (149 mg, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropane 10 (147 mg, 63%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.34 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 8 Hz, 2H), 6.67 (d, J = 8 Hz, 2H), 4.15 (q, J = 7 Hz, 2H), 2.91 (s, 6H), 2.47-2.42 (m, 1H), 1.82-1.77 (m, 1H), 1.54-1.50 (m, 1H), 1.27-1.22 (m, 1H), 1.27 (t, J = 7Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 173.7, 149.4, 127.8, 127.0, 112.8, 60.5, 40.7, 25.7, 23.7, 16.5, 14.2; IR (neat) 2979, 2903, 1713, 1520, 1335, 1176 cm-1; HRMS (FAB) calcd for C14H20NO2 [M+H]+
: 234.1483. Found 234.1488.
OCO2Et
O2N O2N
11
(1R*,2R*)-Ethyl 2-(4-nitrophenyl)cyclopropanecarboxylate (11).15 The title compound was prepared from 4-nitrobenzaldehyde (151 mg, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 11 (139 mg, 59%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.45 (20% EtOAc/hexanes); m.p. 52 °C (litt.: 50 °C); 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 9 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 4.18 (q, J = 7 Hz, 2H), 2.62-2.56 (m, 1H), 2.02-1.96 (m, 1H), 1.75-1.69 (m, 1H), 1.41-1.34 (m, 1H), 1.28 (t, J = 7Hz, 3H) ; 13C NMR (75 MHz, CDCl3) δ 172.4, 148.1, 146.5, 126.6, 123.7, 61.0, 25.6, 25.1, 17.8, 14.2; IR (neat) 2982, 1721,1517, 1343, 1177 cm-1.
O
CO2Et
12
O
O
O
O (1R*,2R*)-Ethyl 2-(benzo[d][1,3]dioxol-6-yl)cyclopropanecarboxylate (12).16 The title compound was prepared from piperonal (150 mg, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 12 (171 mg, 73%) was obtained as a light yellow oil
14 Herbert O. House, H.O.; McDaniel, W. C.; Sieloff, R. F.;Vanderveer D. J. Org. Chem. 1978, 43, 4316-4323. 15 Rasmussen, T.; Jensen, J. F.; Oestergaard, N.; Tanner, D.; Ziegler, T.; Norrby, P.-O. Chem. Eur. J. 2002, 8, 177-184. 16 Yamashita, M.; Okuyama, K.; Ohhara, T.; Kawasaki, I.; Sakai, K. Chem. Pharm. Bull. 1995, 43, 2075-2081.
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after flash chromatography (10% EtOAc/Hexanes). Rf 0.40 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 6.71 (d, J = 10 Hz, 1H), 6.60 (dd, J = 10, 2 Hz, 1H), 6.56 (d, J = 2 Hz, 1H), 5.91 (s, 2H), 4.16 (q, J = 10 Hz, 2H), 2.48-2.42 (m, 1H), 1.83-1.77 (m, 1H), 1.56-1.50 (m, 1H), 1.27 (t, J = 10 Hz, 3H) 1.26-1.19 (m, 1H) ; 13C NMR (75 MHz, CDCl3) δ 173.4, 147.7, 146.1, 133.8, 119.6, 108.1, 106.6, 100.9, 60.6, 26.0, 23.9, 16.7, 14.2; IR (neat) 2890, 1487, 1245, 1039 cm-1.
OCO2Et
13O O
(1R*,2R*)-Ethyl 2-(furan-3-yl)cyclopropanecarboxylate (13). The title compound was prepared from 3-furfuraldehyde (86 µL mg, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropane 13 (128 mg, 71%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.15 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.28 (s, 1H), 6.15 (s, 1H), 4.15 (q, J = 7 Hz, 2H), 2.35-2.30 (m, 1H), 1.77-1.73 (m, 1H), 1.51-1.47 (m, 1H), 1.27 (t, J = 7 Hz, 3H) 1.14-1.09 (m, 1H) ; 13C NMR (100 MHz, CDCl3) δ 173.4, 143.1, 139.1, 124.7, 108.9, 60.6, 22.6, 17.1, 16.1, 14.2; IR (neat) 2981, 2933, 1721, 1323, 1181 cm-1; HRMS (FAB) calcd for C10H13O3 [M+H]+
: 181.0865. Found 181.0866.
O
CO2Et
14
S S
(1R*,2R*)-Ethyl 2-(thiophen-2-yl)cyclopropanecarboxylate (14).16 The title compound was prepared from 2-thiophenecarboxaldehyde (93 µL, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 14 (125 mg, 77%) was obtained as colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.35 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 5 Hz, 1H), 6.90 (dd, J = 5, 4 Hz, 1H), 6.82 (d, J = 4 Hz, 1H), 4.17 (q, J = 7 Hz, 2H), 2.72-2.67 (m, 1H), 1.95-1.90 (m, 1H), 1.64-1.59 (m, 1H), 1.34-1.28 (m, 1H), 1.28 (t, J = 7 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 172.8, 144.1, 126.8, 123.8, 123.0, 60.7, 24.9, 21.4, 17.9, 14.2; IR (neat) 2980, 1721, 1404, 1178, 1045 cm-1.
O
CO2Et
15
TsN
TsN
(1R*,2R*)-Ethyl 2-(1-tosyl-1H-pyrrol-2-yl)cyclopropanecarboxylate (15). The title compound was prepared from 1-tosyl-1H-pyrrole-2-carbaldehyde17 (249 mg, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 15 (273 mg, 82%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.29 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8 Hz, 2H), 7.26-7.21 (m, 3H), 6.10 (t, J = 3Hz, 1H), 5.83 (s, 1H), 4.15 (q, J = 7 Hz, 2H), 2.57-2.52 (m, 1H), 2.36 (s, 3H), 1.58-1.54 (m, 1H), 1.39-1.33 (m, 1H), 1.26 (t, J = 7 Hz, 3H), 1.06-1.01 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.7, 144.8, 136.1, 133.6, 129.9, 127.0, 122.9, 111.3, 110.7, 60.7, 23.3, 21.6, 18.2, 15.1, 14.2; IR (neat) 2981, 2923, 1721, 1366, 1175, 1154, 1055 cm-1; HRMS (FAB) calcd for C17H20NO4S [M+H]+
: 334.1107. Found 334.1101.
NBoc
O
NBoc
CO2Et
16
tert-Butyl 3-(1R*,2R*)-2-(ethoxycarbonyl)cyclopropyl)-1H-indole-1-carboxylate (16). The title compound was prepared from tert-butyl 3-formyl-1H-indole-1-carboxylate18 (245 mg, 1.00 mmol) 17 Masquelin, T.; Broger, E.; Mueller, K.; Schmid, R.; Obrecht, D. Helv. Chim. Acta, 1994, 77, 1395-1411. 18 Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70, 5840-5851.
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
- S 8 -
according to the general procedure A using 10.50 mmol of diazomethane. The desired cyclopropane 16 (227 mg, 69%) was obtained as a light yellow oil after an oxidative work-up and a flash chromatography (5% EtOAc/Hexanes). Rf 0.43 (20% EtOAc/hexanes). The oxidative work-up proceeded as follow: The crude product was dissolved in dichloromethane (10 mL) and cooled to −78°C. The solution was treated with ozone until the solution was blue. Oxygen was then bubbled into the mixture until the blue color had disappeared. Methyl sulfide (1 mL) was added at −78°C and left to warm to room temperature overnight. The solution was concentrated under reduced pressure and the residue was purified by column chromatography. 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J = 7 Hz, 1H), 7.61 (d, J = 8 Hz, 1H), 7.35-7.23 (m, 3H), 4.21 (q, J = 7 Hz, 2H), 2.57-2.50 (m, 1H), 1.92-1.87 (m, 1H), 1.66 (s, 9H), 1.62-1.55 (m, 2H), 1.31 (t, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 149.5, 135.4, 130.4, 124.6, 122.5, 121.9, 120.2, 118.9, 115.2, 83.6, 60.7, 28.1, 21.7, 17.1, 15.3, 14.2. IR (neat) 2976, 1743, 1365, 1150 cm-1; HRMS (FAB) calcd for C19H24NO4 [M+H]+
: 330.1699. Found 330.1695.
OCO2Et
N N17
(1R*,2R*)-Ethyl 2-(pyridin-2-yl)cyclopropanecarboxylate (17).10 The title compound was prepared from 2-pyridinecarboxaldehyde (95 µL mg, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 17 (117 mg, 61%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.25 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 8.43-8.41 (m, 1H), 7.56-7.50 (m, 1H), 7.20 (d, J = 8 Hz, 1H), 7.08-7.03 (m, 1H), 4.14 (q, J = 7 Hz, 2H), 2.59-2.52 (m, 1H), 2.25-2.19 (m, 1H), 1.63-1.54 (m, 2H), 1.25 (t, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.3, 158.8, 149.3, 135.9, 122.4, 121.2, 60.6, 27.1, 24.2, 17.2, 14.1; IR (neat) 2981, 1721, 1595, 1475, 1329, 1178 cm-1.
O
O
O CO2Et
O
O CO2Et
CO2Et
19
3 3
18
(1R*,2R*)-Ethyl 2-(2-(3-(ethoxycarbonyl)propoxy)-5-acetylphenyl) cyclopropanecarboxylate (19). The title compound was prepared from ethyl 4-(4-acetyl-2-formylphenoxy)butanoate 1819 (278 mg, 1.00 mmol) according to the general procedure A using 7.50 mmol of diazomethane. The desired cyclopropanes 19 (188 mg, 52%) was obtained as a light yellow oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.43 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 12, 3 Hz, 1H), 7.58 (d, J = 3 Hz, 1H), 6.84 (d, J = 12 Hz, 1H), 4.23-4.08 (m, 6H), 2.68-2.61 (m, 1H), 2.52 (s, 3H), 2.51 (t, J = 10 Hz, 2H), 2.19-2.10 (m, 2H), 1.81-1.75 (m, 1H), 1.59-1.53 (m, 1H), 1.40-1.33 (m, 1H), 1.28 (t, J = 10 Hz, 3H), 1.24 (t, J = 10 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.7, 173.5, 172.9, 161.5, 129.8, 129.2, 128.6, 126.7, 110.1, 67.1, 60.6, 60.4, 30.4, 26.2, 24.4, 22.4, 21.2, 14.9, 14.2, 14.1. IR (neat) 2980, 1725, 1676, 1601, 1259, 1182; HRMS (FAB) calcd for C20H27O6 [M+H]+: 363.1802. Found 363.1812.
OCO2Me
20
(1R*,2R*)-Methyl 2-phenylcyclopropanecarboxylate (20).20 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure A using 6.00 mmol of diazomethane. The desired cyclopropane 20 (143 mg, 81%) was obtained as a colorless oil after flash 19 Kahnberg, P.; Lee, C. W.; Grubbs, R. H.; Sterner, O. Tetrahedron 2002, 58, 5203-5208. 20 Walser, P.; Renold, P.; N'Goka, V.; Hosseinzadeh, F.; Tamm, C. Helv. Chim. Acta 1991, 74, 1941-1952.
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
- S 9 -
chromatography (5% EtOAc/Hexanes). Rf 0.29 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.22-7.20 (m, 1H), 7.11-7.09 (m, 2H), 3.72 (s, 3H), 2.56-2.51 (m, 1H), 1.93-1.89 (m, 1H), 1.63-1.58 (m, 1H), 1.35-1.30 (m, 1H) ; 13C NMR (100 MHz, CDCl3) δ 173.8, 139.9, 128.4, 126.4, 126.1, 51.8, 26.2, 23.9, 16.9; IR (neat) 3029, 2951, 1724, 1440, 1197, 1171 cm-1.
OCO2
tBu
21
(1R*,2R*)-tert-Butyl 2-phenylcyclopropanecarboxylate (21).21 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure C using 6.00 mmol of diazomethane. The desired cyclopropane 21 (161 mg, 74%) was obtained as a colorless oil after flash chromatography (5% EtOAc/Hexanes). Rf 0.34 (10% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 7.21-7.17 (m, 1H), 7.10-7.08 (m, 2H), 2.46-2.41 (m, 1H), 1.85-1.81 (m, 1H), 1.55-1.50 (m, 1H), 1.46 (s, 9H), 1.25-1.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.5, 140.5, 128.4, 126.2, 126.0, 80.5, 28.1, 25.7, 25.2, 17.0; IR (neat) 2977, 1705, 1637, 1328, 1314, 1148 cm-1.
OCOPh
22
Phenyl((1R*,2R*)-2-phenylcyclopropyl)methanone (22).22 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure B using 6.00 mmol of diazomethane. The desired cyclopropane 22 (162 mg, 73%) was obtained as a yellow solid after flash chromatography (5% EtOAc/Hexanes). Rf 0.53 (20% EtOAc/hexanes); m.p. 44 °C (litt. 45-47 °C);23 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7 Hz, 2H), 7.58-7.54 (m, 1H), 7.48-7.44 (m, 2H), 7.33-7.30 (m, 2H), 7.26-7.17 (m, 3H), 2.93-2.89 (m, 1H), 2.73-2.68 (m, 1H), 1.95-1.91 (m, 1H), 1.59-1.54 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 198.5, 140.4, 137.7, 132.8, 128.5 (2C), 128.0, 126.5, 126.2, 29.9, 29.2, 19.2; IR (neat) 2980, 1711, 1627, 1272, 1164 cm-1.
OCONMe2
23
(1R*,2R*)-N,N-dimethyl-2-phenylcyclopropanecarboxamide (23).24 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure B using 4.50 mmol of diazomethane. The desired cyclopropane 23 (155 mg, 82%) was obtained as a colorless solid after flash chromatography (50% EtOAc/Hexanes). Rf 0.19 (50% EtOAc/hexanes); m.p. 59 °C (litt. 61 °C);10 1H NMR (300 MHz, CDCl3) δ 7.31-7.12 (m, 5H), 3.14 (s, 3H), 3.00 (s, 3H), 2.52-2.45 (m, 1H), 2.03-1.97 (m, 1H), 1.68-1.61 (m, 1H), 1.30-1.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.8, 141.0, 128.4, 126.1, 126.0, 37.2, 35.8, 25.4, 23.1, 16.2.; IR (neat) 3028, 2930, 1634, 1496, 1417, 1139 cm-1.
OCON(OMe)Me
24
(1R*,2R*)-N-methoxy-N-methyl-2-phenylcyclopropanecarboxamide (24).25 The title compound was prepared from benzaldehyde (102µL, 1.00 mmol) according to the general procedure C using 4.50 mmol of diazomethane. The desired cyclopropane 24 (181 mg, 88%) was obtained as a pale yellow oil after flash chromatography (50% EtOAc/Hexanes). Rf 0.22 (80% EtOAc/hexanes). M.p. 59 °C. 1H
21 Lyle, M. P. A.; Wilson, P. D. Org. Lett. 2004, 6, 855-858. 22 Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J. Org. Chem. 1997, 62, 2337-2343. 23 Wessig, P.; Muhling, O. Helv. Chim. Acta, 2003, 86, 865-893. 24 Doyle, M. P.; Loh, K.-L.; DeVries, K. M.; Chinn, M. S. Tetrahedron Lett. 1987, 28, 833-836. 25 Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org. Chem. 2004, 69, 8984-8986.
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
- S 10 -
NMR (300 MHz, CDCl3) δ 7.30-7.12 (m, 5H), 3.69 (s, 3H), 3.23 (s, 3H), 2.53-2.39 (m, 2H), 1.66-1.60 (m, 1H), 1.34-1.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 173.0, 140.7, 128.4, 126.26, 126.20, 61.7, 32.5, 25.9, 21.5, 16.5; IR (neat) 2936, 2241, 1650, 1437, 1274, 1176, 1119, 995, 910, 728 cm-1.
OP(O)(OMe)2
25
(1R*,2R*)-Dimethyl 2-phenylcyclopropylphosphonate (25).26 The title compound was prepared from benzaldehyde (102 µL, 1.00 mmol) according to the general procedure B using 4.50 mmol of diazomethane. The desired cyclopropane 25 (156 mg, 69%) was obtained as a yellow oil after flash chromatography (80% EtOAc/Hexanes). Rf 0.31 (100% EtOAc). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.22-7.18 (m, 1H), 7.11 (d, J = 7 Hz, 2H), 3.79 (d, J = 8 Hz, 3H), 3.76 (d, J = 8 Hz, 3H), 2.53-2.44 (m, 1H), 1.54-1.45 (m, 1H), 1.30-1.22 (m, 1H), 1.16-1.10 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 139.8 (d, J = 3 Hz), 128.5, 126.6, 126.1, 52.7 (d, J = 8 Hz), 20.9 (d, J = 5 Hz), 13.8 (d, J = 192 Hz), 12.4 (d, J = 6 Hz); 31P NMR (121 MHz, CDCl3) δ 23.1; IR (neat) 2952, 2851, 1459, 1244, 1027 cm-1. SYNTHESIS OF CYCLOPROPANECARBOXYLIC ACID 31.
OCO2Et
BocHNBocHN2726
tert-Butyl 4-((1R*,2R*)-2-(ethoxycarbonyl)cyclopropyl)phenylcarbamate (27). The title compound was prepared from 4-(tert-butoxycarbonylamino)benzaldehyde (26)27 (221 mg, 1.00 mmol) according to the general procedure A using 4.50 mmol of diazomethane. The desired cyclopropane 27 (256 mg, 84%) was obtained as a colorless oil after flash chromatography (10% EtOAc/Hexanes). Rf 0.26 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8 Hz, 2H), 7.01 (d, J = 8 Hz, 2H), 6.44 (s(br), 1H), 4.15 (q, J = 7 Hz, 2H), 2.49-2.44 (m, 1H), 1.85-1.80 (m, 1H), 1.57-1.53 (m, 1H), 1.50 (s, 9H), 1.29-1.25 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 173.4, 152.6, 136.7, 134.6, 126.7, 118.6, 80.4, 60.6, 28.3, 25.7, 23.9, 16.8, 14.2; IR (neat) 3265, 2974, 1728, 1518, 1155 cm-1; HRMS (FAB) calcd for C17H23NO4Na [M+Na]+
: 328.1519. Found 328.1514.
H2N
CO2EtCO2Et
BocHN
27
(1R*,2R*)-Ethyl 2-(4-aminophenyl)cyclopropanecarboxylate. To a solution of 27 (200 mg, 0.65 mmol) in DCM (4 mL) at 0 °C, was added TFA (2 mL). The resulting mixure was warmed at RT and stirred for 2 hours. The mixture was diluted with DCM (10 mL) then washed with 10% aqueous K2CO3 (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% MeOH/DCM). Rf 0.32 (20% MeOH/DCM). The free amine was obtained as a yellow oil (113 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 9 Hz, 2H), 6.60 (d, J = 9 Hz, 2H), 4.15 (q, J = 7 Hz, 2H), 3.60 (s (br), 2H), 2.45-2.40 (m, 1H), 1.81-1.76 (m, 1H), 1.54-1.49 (m, 1H), 1.27 (t, J = 7 Hz, 3H), 1.25-1.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.6, 144.9, 129.8, 127.2, 115.1, 60.5, 25.8, 23.7, 16.5, 14.2; IR (neat) 3352, 2943, 1679, 1501, 1247 cm-1; HRMS (FAB) calcd for C12H16NO2 [M+H]+
: 206.1175. Found 206.1174.
26 Charette, A.B.C.; Bouchard, J.-E. Can. J. Chem. 2005, 83, 533-542. 27 Niimi, T.; Orita, M.; Okazawa-Igarashi, M.; Sakashita, H.; Kikuchi, K.; Ball, E.; Ichikawa, A.; Yamagiwa, Y.; Sakamoto, S.; Tanaka, A.; Tsukamoto, S.; Fujita, S.; Tatsuta, K.; Maeda, Y.; Chikauchi, K. J. Med. Chem. 2001, 44, 4737-4740.
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
- S 11 -
NH
CO2Et
PhO29
H2N
CO2Et
(1R*,2R*)-Ethyl 2-(4-(3-phenoxybenzylamino)phenyl)cyclopropanecarboxylate (29). A mixture of (1R*,2R*)-ethyl 2-(4-aminophenyl)cyclopropanecarboxylate (80 mg, 0.39 mmol) and 3-(phenyloxy)benzaldehyde (93 mg, 0.47 mmol) in DCE (4 mL) was heated at 80 °C for 2 hours then cooled to RT. Acetic acid (1 drop) and NaHB(OAc)3 (123 mg, 0.58 mmol) were added and the reaction was stirred until the reaction was completed by TLC analysis. The mixture was diluted with DCM (10 mL) and washed with water (20 mL), dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (25% EtOAc/hexane). Rf 0.44 (50% EtOAc/hexane). The desired product was obtained as a yellow oil (117 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 3H), 7.12-6.87 (m, 8H), 6.53 (d, J = 8 Hz, 2H), 4.29 (s, 2H), 4.15 (q, J = 7 Hz, 2H), 4.02 (br, 1H), 2.46-2.39 (m, 1H), 1.80-1.75 (m, 1H), 1.54-1.48 (m, 1H), 1.27 (t, J = 7 Hz, 3H), 1.25-1.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.7, 157.5, 156.9, 146.5, 141.5, 129.8, 129.7, 128.8, 127.2, 123.2, 122.0, 118.9, 117.6, 117.4, 112.9, 60.5, 48.0, 25.8, 23.7, 16.5, 14.2; IR (neat) 2930, 1685, 1494, 1255 cm-1; HRMS (FAB) calcd for C25H26NO3 [M+H]+: 388.1899. Found 388.1907.
NH
CO2H
PhO31N
H
CO2Et
PhO29
(1R*,2R*)-2-(4-(3-Phenoxybenzylamino)phenyl)cyclopropanecarboxylic acid (31). To solution of 29 (90 mg, 0.23 mmol) in MeOH (10 mL), was added a 25% aqueous NaOH solution (1 mL). The resulting mixture was heated under reflux overnight. The solution was diluted with water (5 mL) and the pH was adjusted to 3-4 with a saturated NaHSO3 solution. The mixture was washed with DCM (10 mL) and the organic layer was dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (10% MeOH/DCM). Rf 0.29 (20% MeOH/DCM). The desired product 31 was obtained as a gum (77 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.27 (m, 3H), 7.12-7.01 (m, 2H), 7.01-6.98 (m, 3H), 6.94-6.88 (m, 3H), 6.54 (d, J = 9 Hz, 2H), 4.29 (s, 2H), 2.54-2.49 (m, 1H), 1.80-1.76 (m, 1H), 1.60-1.56 (m, 1H), 1.35-1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 179.6, 157.5, 156.9, 146.7, 141.4, 129.9, 129.7, 128.3, 127.3, 123.2, 122.0, 118.9, 117.6, 117.4, 112.9, 48.0, 26.8, 23.5, 17.0; IR (neat) 2922, 1691, 1488, 1248, 1218, 735 cm-1; HRMS (FAB) calcd for C23H22NO3 [M+H]+
: 360.1585. Found 360.1594. SYNTHESIS OF CYCLOPROPANECARBOXAMIDE 30.
O
BocHN
BocHN
N
O
28
tert-Butyl 4-((1R*,2R*)-2-(dimethylcarbamoyl)cyclopropyl)phenylcarbamate (28). The title compound was prepared from 4-(tert-butoxycarbonylamino)benzaldehyde27 according to the general procedure C using 9.00 mmol of diazomethane. The desired cyclopropane 28 (219 mg, 72%) was obtained as a colorless oil after flash chromatography (50% EtOAc/hexane). Rf 0.15 (10% EtOAc/DCM). 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J = 9 Hz, 2H), 7.03 (d, J = 9 Hz, 2H), 6.47 (br, 1H), 3.11 (s, 3H), 2.98 (s, 3H), 2.45-2.38 (m, 1H), 1.94-1.88 (m, 1H), 1.63-1.57 (m, 1H), 1.50 (s, 9H), 1.25-1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.4, 152.6, 136.7, 134.6, 126.7, 118.6, 80.4, 60.6,
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
- S 12 -
28.3, 25.7, 23.9, 16.8, 14.2; IR (neat) 3283, 2980, 1721, 1631, 1527, 1162 cm-1; HRMS (FAB) calcd for C17H25N2O3 [M+H]+
: 304.1786. Found 304.1852.
BocHN
N
O
28H2N
N
O
(1R*,2R*)-2-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide. To a solution of 28 (88 mg, 0.29 mmol) in DCM (2 mL) at 0 °C, was added TFA (1 mL). The resulting mixture was warmed at RT and stirred for 2 hours. The mixture was diluted with DCM (10 mL), then washed with 10% aqueous K2CO3 (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% MeOH/DCM). Rf 0.46 (20% MeOH/DCM). The free amine was obtained as a yellow oil (56 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 6.93 (d, J = 8 Hz, 2H), 6.61 (d, J = 8 Hz, 2H), 3.58 (s (br), 2H), 3.12 (s, 3H), 2.98 (s, 3H), 2.41-2.35 (m, 1H), 1.90-1.84 (m, 1H), 1.58-1.52 (m, 1H), 1.20-1.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 144.6, 130.9, 127.1, 115.1, 37.2, 35.8, 25.0, 22.7, 15.6; IR (neat) 3341, 3228, 3006, 2929, 1622, 1519, 1285, 1141 cm-1; HRMS (FAB) calcd for C12H17N2O [M+H] +: 205.1337. Found 205.1340.
H2N
N
O
NH
N
O
PhO30
(1R*,2R*)-2-(4-(3-phenoxybenzylamino)phenyl)-N,N-dimethylcyclopropanecarboxamide (30). To a mixture of (1R*,2R*)-2-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide (80 mg, 0.39 mmol), 3-(phenyloxy)benzaldehyde (93 mg, 0.47 mmol) and acetic acid (1 drop) in DCE (4 mL) was added NaHB(OAc)3 (123 mg, 0.58 mmol). The reaction was stirred at RT until the reaction was completed by TLC analysis (2 hours). The mixture was diluted with DCM (10 mL) then washed with water (20 mL), dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (10% MeOH/DCM). Rf 0.32 (20% MeOH/DCM). The desired product 30 was obtained as a yellow oil (128 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 3H), 7.13-7.08 (m, 2H), 7.02-6.88 (m, 6H), 6.54 (d, J = 8 Hz, 2H), 4.28 (s, 2H), 4.05 (br, 1H), 3.11 (s, 3H), 2.98 (s, 3H), 2.40-2.35 (m, 1H), 1.89-1.85 (m, 1H), 1.58-1.53 (m, 1H), 1.20-1.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 157.5, 156.9, 146.3, 141.5, 129.9, 129.8, 129.7, 127.1, 123.2, 122.0, 118.8, 117.6, 117.4, 112.9, 48.1, 37.2, 35.8, 25.0, 22.6, 15.6; IR (neat) 3336, 2926, 1615, 1523, 1486, 1247 cm-1; HRMS (FAB) calcd for C25H27N2O2 [M+H]+
: 387.2079. Found 387.2072.
Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2008
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.3087.2857.2607.2257.2017.1777.1137.090
4.2104.1864.1624.1382.5542.5402.5322.5232.5192.5092.5022.4881.9361.9221.9191.9081.9051.8941.8911.877
1.6351.6191.6171.6011.5891.5871.5711.3461.3311.3251.3181.3071 297
2.01
1.00
1.01
1.09
3.99
2.003.27
CD
Cl3, 300 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
2.00
1.9361.9221.9191.9081.9051.8941.8911.877
1.6351.6191.6171.6011.5891.5871.571
1.3461.3311.3251.3181.3071.2971.2831.260
O
O
S13
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.396
140.095
128.432126.432126.120
77.42377.00076.576
60.685
26.15424.181
17.06814.253
O
O
S14
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.8877.8837.8687.8647.4467.4427.4277.4247.4087.4047.3057.3037.2867.2847.2687.2647.2607.1417.121
4.2304.2124.1944.1763.8823.1443.1333.1273.1213.1153.1103.1043.093
1.7821.7691.7611.7581.7481.7371.6321.6191.6071.5961.5841.3651.3541.3481.3451.3371.3331.3271.3171 300
1.00
1.021.061.02
2.01
2.98
0.99
1.000.98
0.98 3.08
CD
Cl3, 400 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
1.7821.7691.7611.7581.748
1.7371.6321.619
1.607
1.596
1.584
1.365
1.3541.3481.3451.3371.3331.3271.3171.3001.282
CD
Cl3, 400 M
Hz
7.007.10
7.207.30
7.407.50
7.607.70
7.807.90
8.00
7.8877.8837.8687.864
7.4467.4427.4277.4247.4087.4047.3057.3037.2867.2847.2687.2647.260
7.1417.121
CO
2 Et
CO
2 Me
S15
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.539
167.938
140.559
131.972131.414130.581127.250126.608
77.42477.00076.576
60.593
52.109
25.41123.379
15.68614.314
CO
2 Et
CO
2 Me
S16
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.3827.3517.2607.1917.1727.1537.0256.994
4.2354.2114.1874.1642.7832.7682.7612.7532.7462.7382.7302.7151.8441.8271.8161.8121.7991.7841.6551.6401.6231.6101.5921.3531.3381.3311.3251.3181.3101.3021 271
1.00
0.992.05
2.04
0.97
1.011.02
4.02
CD
Cl3, 300 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.90
1.844
1.8271.8161.8121.7991.784
1.6551.6401.6231.6101.592
1.3531.3381.3311.3251.318
1.3101.302
1.2941.271
Cl
CO
2 Et
S17
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.286
137.425135.610129.329127.813127.060126.712
77.42477.00076.576
60.732
24.206
22.906
15.526
14.291
Cl
CO
2 Et
S18
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.5767.5727.5507.5467.2607.2337.2297.2087.2047.1197.1147.0947.0887.0687.0637.0337.0287.0077.003
4.2474.2234.2004.1762.7412.7262.7192.7112.7042.6962.6892.6741.8211.8041.7931.7891.7761.7611.6571.6411.6251.6111.594
1.3601.3451.3381.3321.3211.3101.2981 274
1.00
1.481.01 1.00
2.00
0.97
1.021.05
4.05
CD
Cl3, 300 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.90
1.8211.8041.7931.7891.776
1.761
1.657
1.6411.6251.6111.594
1.360
1.345
1.3381.3321.3211.3101.298
1.274
Br
CO
2 Et
S19
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.270
139.044
132.592128.158127.490127.332126.261
77.42377.00076.576
60.720
26.989
23.142
15.68514.327
Br
CO
2 Et
S20
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.2607.2137.1947.1746.7586.7386.6976.6786.645
4.1944.1774.1594.141
3.7922.5152.5052.5032.5002.4902.4822.4782.4661.9231.9101.8991.8891.8781.6101.5971.5851.5741.5621.3281.3121.3071.2971.2791.261
1.00
1.01 1.01 1.02
1.98
3.02
1.00
0.98
1.00
4.00
CD
Cl3, 400 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50
2.602.70
2.80
2.5152.5052.5032.5002.4902.4822.4782.466
1.9231.9101.8991.8891.878
1.6101.5971.5851.5741.5621.3281.3121.3071.2971.2791.261
MeO
CO
2 Et
S21
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
173.356
159.682
141.790
129.447
118.403
112.077111.692
77.31877.00076.682
60.701
55.173
26.16524.188
17.079
14.250
MeO
CO
2 Et
S22
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.260
7.1047.0777.0086.981
4.2014.1774.1534.1292.5212.5062.4992.4892.4852.4762.4682.4542.3151.8911.8771.8731.8631.8591.8491.8451.8311.6021.5871.5801.5701.5561.5391.3111.3011.2771 2531 247
2.01 2.00
1.98
1.003.00
0.97
1.20
4.04
CD
Cl3, 300 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
1.8911.8771.8731.8631.8591.8491.8451.831
1.6021.5871.5801.5701.5561.539
1.3111.3011.2771.2531.247
0.97
1.20
4.04
CO
2 Et
S23
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.529
137.023136.061
129.107126.068
77.42377.00076.577
60.642
25.93024.05520.984
16.955
14.265
CO
2 Et
S24
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
7.2497.2287.0347.013
4.1954.1784.1604.142
2.5072.4972.4912.4832.4742.4682.4581.8821.8701.8601.8501.8381.6201.6081.5961.5851.5731.2971.2791.2621.242
2.04
2.03
2.00
0.98
1.00
1.14
4.05
CO
2 Et
Cl
S25
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.099
138.606
132.135128.528127.535
77.31777.00076.682
60.793
25.475
24.159
17.00414.237
CO
2 Et
Cl
S26
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.4037.3757.2606.9816.953
4.2034.1794.1554.1312.5012.4872.4802.4702.4662.4572.4492.4351.8921.8741.8631.8601.8501.8461.8321.6301.6141.5971.5841.5661.3031.2791.2721.2631.255
1.97
2.03
2.00
0.97
0.99
1.05
4.02
CD
Cl3, 300 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40
2.502.60
2.5012.4872.4802.4702.4662.4572.4492.435
1.8921.874
1.8631.860
1.8501.8461.832
1.6301.6141.5971.5841.566
1.3031.2791.2721.2631.2551.235
Br
CO
2 Et
S27
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.111
139.144
131.463127.899
120.101
77.42477.00076.576
60.823
25.54224.159
17.00714.230
Br
O
O
S28
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.2607.0497.0216.8366.807
4.2024.1784.1544.1303.7832.5142.5012.4932.4832.4792.4702.4622.4481.8531.8391.8351.8251.8221.8111.8081.7941.5851.5701.5541.5391.5221.3031.2791.2711.2631.2551 2491 221
1.991.96
2.00
2.97
0.98
1.00
1.03
4.03
CD
Cl3, 300 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
2.00
1.8531.8391.8351.8251.8221.8111.8081.794
1.5851.5701.5541.5391.522
1.3031.279
1.2711.2631.2551.2491.2431.2361.221
O
O
MeO
S29
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.530
158.262
132.031
127.308
113.852
77.42477.00076.576
60.609
55.276
25.60223.852
16.73014.250
O
O
MeO
S30
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
7.260
7.0076.9866.6846.663
4.1834.1654.1474.1292.9132.4762.4662.4602.4532.4502.4432.4372.4271.8201.8091.8071.7991.7971.7891.7861.7761.5471.5361.5341.5241.5131.5111.5001.2891.2711.2601.2531.2441.2391.2341 223
1.99
2.01
2.00
6.00
0.94
0.90
1.07
4.02
CD
Cl3, 400 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
1.8201.8091.8071.7991.7971.7891.7861.776
1.5471.5361.5341.5241.5131.5111.500
1.2891.2711.260
1.2531.2441.2391.2341.223
N
CO
2 Et
S31
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.792
149.487
127.861127.060
112.825
77.31777.00076.682
60.517
40.778
25.78223.732
16.56014.285
N
CO
2 Et
S32
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
8.1578.127
7.2607.2367.207
4.2224.1984.1754.1512.6242.6192.6132.6052.5912.5822.5752.5612.0292.0152.0112.0011.9971.9871.9821.9681.7551.7391.7251.7211.7081.6901.4141.3981.3931.3851.3771.3691.3641 3481 3131 289
2.01
2.00
2.10
0.96
1.00
1.01
0.99 3.05
CD
Cl3, 300 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.0292.0152.0112.0011.9971.9871.9821.968
1.7551.7391.7251.7211.7081.690
1.4141.3981.3931.385
1.3771.3691.3641.3481.3131.2891.266
O2 N
O
O
S33
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
172.452
148.136146.513
126.697123.770
77.42377.00076.576
61.091
25.68125.124
17.86914.211
O2 N
O
O
S34
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.2606.7286.7026.6216.6156.5946.5896.5636.5575.919
4.1944.1704.1474.1232.4882.4742.4672.4572.4532.4442.4362.4221.8341.8201.8171.8061.8031.7921.7891.7751.5691.5541.5521.5381.5371.5231.5211.5061.2981.2741.2621.2501.2401 2341 2251 2181 2121 197
1.001.02 0.97
2.02
1.99
1.00
1.02
1.02
4.37
CD
Cl3, 400 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.90 1.8341.8201.817
1.8061.803
1.7921.7891.775
1.5691.5541.5521.5381.5371.5231.5211.506
1.2981.2741.262
1.250
1.2401.2341.2251.2181.2121.197
O
O
OO
S35
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.410
147.742146.166
133.888
119.658
108.143106.614
100.942
77.42477.00076.576
60.684
26.06723.922
16.76614.240
O
O
OO
S36
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.3247.2897.260
6.155
4.1844.1664.1484.1302.3532.3422.3372.3282.3202.3142.304
1.7771.7651.7551.7451.7331.5821.5171.5051.4941.4821.4711.2941.2761.2581.1451.1341.1291.1241.1181 097
1.00 0.99
0.97
1.98
1.01
0.99
0.983.031.00
CD
Cl3, 400 M
Hz
0.901.00
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40 2.353
2.3422.3372.3282.3202.3142.304
1.777
1.7651.755
1.745
1.733
1.5821.517
1.505
1.494
1.482
1.471
1.2941.2761.2581.145
1.1341.1291.1241.1181.1141.108
1.097
CO
2 Et
O
S37
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
173.413
143.118139.167
124.719
108.916
77.31777.00076.682
60.680
22.67717.18616.10914.250
CO
2 Et
O
S38
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.2607.0997.086
6.9126.9036.8996.8906.8276.818
4.1994.1814.1634.1452.7242.7142.7092.7012.6922.6872.676
1.9501.9391.9371.9281.9271.9181.9161.9051.6431.6301.6191.6081.5961.3461.3411.3291.3201.3141.303
1.021.00 0.97
1.97
1.01
1.00
1.02
3.96
CD
Cl3, 400 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40
2.502.60
2.702.80 2.724
2.7142.7092.7012.6922.6872.676
1.9501.9391.9371.9281.9271.9181.9161.905
1.6431.6301.6191.6081.596
1.3461.3411.3291.3201.3141.3031.2851.268
SC
O2 Et
S39
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
172.843
144.182
126.833
123.868123.062
77.31877.00076.682
60.795
24.94421.44717.90414.232
SC
O2 Et
S40
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.6627.6427.2607.2397.216
6.1106.1026.0945.837
4.1764.1584.1414.1232.5732.5562.5482.5392.5242.3681.5891.5771.5661.5561.5441.3971.3851.3741.3631.3511.3321.2801.2621.245
1.0681.0571.0511.0471.0401 0361 0311 019
1.97
3.21
0.98
1.04
1.99
0.983.03
1.061.003.051.00
CD
Cl3, 400 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.5891.5771.5661.5561.544
1.3971.3851.3741.3631.3511.332
1.2801.2621.245
1.0681.0571.0511.0471.0401.0361.0311.019
1.06
1.00
3.05
1.00
NTsC
O2 Et
S41
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
172.716
144.874
136.104133.662129.936127.089122.967
111.320110.734
77.42477.00076.576
60.707
23.34821.62818.26815.17114.281
NTsC
O2 Et
S42
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
8.1198.0947.6227.596
7.3597.3547.3347.3307.3077.3027.2867.2817.2607.2367.232
4.2484.2244.2014.177
2.5712.5452.5362.5152.5011.9291.9131.9011.8851.8711.6621.6231.5921.5541.3361.3121.288
1.00
1.03
3.34
2.02
1.01
0.97
9.12 2.02
3.04
CD
Cl3, 300 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50
2.60 2.571
2.5452.5362.5152.501
1.9291.9131.9011.8851.871
1.662
1.6231.592
1.554
1.3361.3121.288
N
CO2 Et
OO
S43
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.604
149.595
135.405
130.424
124.635122.565121.942120.257
118.994115.259
83.657
77.42477.00076.576
60.731
28.169
21.728
17.13915.34114.281
N
CO
2 Et
OO
S44
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
8.4308.4288.4148.4127.5667.5607.5407.5347.5157.5097.2607.2197.1937.0817.0787.0657.0627.0567.0537.0407.037
4.1804.1564.1334.1092.5902.5772.5692.5602.5572.5472.5402.5272.2582.2452.2392.2302.2272.2172.2122.199
1.6361.6241.6011.5711.5521.5401.2781.2541.230
1.00
0.97
1.02
1.02
2.01
0.99
2.02
0.99
3.02
CD
Cl3, 400 M
Hz
1.201.30
1.401.50
1.601.70
1.80
1.6361.6241.601
1.5711.5521.540
1.2781.2541.230
2.02
3.02
NC
O2 Et
S45
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.321
158.823
149.360
135.923
122.434
121.219
77.42477.00076.576
60.634
27.16124.296
17.25114.195
NC
O2 Et
S46
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.8227.8157.7937.7867.5907.583
7.2606.8556.826
4.2324.1964.1724.1484.1244.1014.0822.6832.6682.6602.6532.6452.6382.6302.615
2.5422.5292.5182.4942.1902.1462.1021.8121.7951.7841.7801.7671.752
1.5921.5771.5611.5461.5301.4011.3861.3781.3741.3641.3591 3511 3361 3081 2481 224
1.00
1.05
1.03
6.17
0.965.13
1.99
1.010.961.036.04
CD
Cl3, 400 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
1.8121.7951.7841.780
1.7671.752
1.5921.5771.5611.5461.530
1.4011.3861.3781.3741.3641.3591.3511.3361.3081.2841.2721.2601.2481.224
O
CO
2 Et
OC
O2 Et
S47
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
196.737
173.591172.961
161.575
129.852129.228128.601126.743
110.105
77.42477.00076.576
67.103
60.63760.476
30.42226.27124.43022.469
21.21014.93214.25514.181
O
CO
2 Et
OC
O2 Et
S48
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
7.3067.3037.2867.2677.2607.2297.2257.2227.2077.1897.1167.1127.0957.093
3.724
2.5612.5512.5452.5382.5352.5282.5222.5121.9381.9271.9241.9171.9141.9061.9031.8931.6361.6251.6231.6131.6121.6021.6001.5891.3571.3461.3411.3361.3301.3251 320
1.03
1.02
0.98
0.98
3.00
1.990.972.03
CD
Cl3, 400 M
Hz
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40
2.502.60 2.561
2.5512.5452.5382.5352.5282.5222.512
1.9381.9271.9241.9171.9141.9061.9031.893
1.6361.6251.6231.6131.6121.6021.6001.589
1.3571.3461.3411.3361.3301.3251.3201.309
O
O
S49
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.822
139.948
128.443126.481126.168
77.31877.00076.682
51.873
26.24523.915
16.992
O
O
S50
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
7.2957.2787.2607.2157.2117.1937.1757.1037.1007.082
2.4622.4522.4462.4392.4362.4292.4232.4131.8591.8481.8451.8381.8351.8271.8241.8141.5561.5451.5321.5221.5081.4691.2581.2471.2421.2371.2311.2261.2211 210
2.101.002.85
0.99
1.02
1.01 9.03
1.06
CD
Cl3, 400 M
Hz
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50
2.60
2.462
2.4522.4462.4392.4362.4292.423
2.413
1.859
1.8481.8451.8381.8351.8271.824
1.814
1.556
1.5451.532
1.5221.5081.469
1.258
1.2471.2421.2371.2311.2261.221
1.210
O
O
S51
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
172.546
140.504
128.397126.294126.052
80.54177.31877.00076.683
28.16025.72825.283
17.043
O
O
S52
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
8.0107.9927.5847.5667.548
7.4867.4667.4487.3397.3217.3027.2607.2567.237
7.179
2.9352.9252.9222.9152.9112.9042.9012.8912.7342.7242.7172.7112.7082.7012.6952.685
1.9581.9481.9451.9351.9251.9231.9121.5901.5801.5741.5701.5641.5601.5541.543
0.99
0.98
1.00
1.01
1.99
0.972.001.993.01
O
S53
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
198.545
140.470137.717
132.890128.546128.097126.588126.214
77.31977.00076.682
29.99429.278
19.226
O
S54
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.3047.2817.2607.2567.2147.1897.1657.1367.1317.108
3.1282.993
2.5122.4982.4912.4812.4772.4682.4612.4472.0212.0062.0031.9931.9891.9791.9761.9611.6691.6551.6511.6381.6251.6211.6071.2961.2821.2751.2681.2611 2541 2481 233
1.03
1.02
0.98
3.003.02
0.96
5.90
CD
Cl3, 300 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50
2.60 2.5122.4982.4912.4812.4772.4682.4612.447
2.0212.0062.0031.9931.9891.9791.9761.961
1.6691.6551.6511.6381.6251.6211.607
1.2961.2821.2751.2681.2611.2541.2481.233
N
O
S55
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
171.886
141.096
128.409126.160126.061
77.42477.00076.576
37.28535.857
25.47223.157
16.255
N
O
S56
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.3097.2867.2607.2207.1967.1507.1457.122
3.6933.2392.5372.5232.5162.5022.4932.4862.4722.4362.3971.6631.6491.6451.6321.6191.6151.6011.3421.3281.3211.3151.3071.3011.2931.279
2.98
3.01
5.12
0.99
0.980.99
1.00
CD
Cl3, 300 M
Hz
1.001.50
2.002.50
2.5372.5232.5162.5022.4932.4862.4722.4362.397
1.6631.6491.6451.6321.6191.6151.6011.3421.3281.3211.3151.3071.3011.2931.279
N
O
O
S57
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.092
140.783
128.422126.260126.204
77.42377.00076.577
61.700
32.551
25.902
21.559
16.507
N
O
O
S58
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.3037.2857.2667.2607.2247.2057.1877.1237.105
3.7993.7803.7723.7532.5382.5252.5172.5102.5022.4852.4762.4702.4622.4481.5491.5371.5111.5021.4751.4641.4531.3091.2951.2861.2591.2421.2281.1681.1551.1441 1281 118
2.98 3.00
1.02
1.021.031.01
2.00 1.01 2.01
CD
Cl3, 400 M
Hz
0.901.00
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40
2.502.60 2.538
2.5252.5172.5102.5022.4852.4762.4702.4622.448
1.5491.5371.5111.5021.4751.4641.453
1.3091.2951.2861.2591.2421.2281.1681.155
1.1441.128
1.1181.104
P OO
Me
OM
e
S59
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
139.834139.804
128.568126.606126.181
77.31676.99776.679
52.70052.640
20.98520.94014.72112.80612.45612.395
P O
OM
eO
Me
S60
CD
Cl3, 121 M
Hz
-140-130
-120-110
-100-90
-80-70
-60-50
-40-30
-20-10
010
2030
4050
6070
8090
100110
120130
140
23.188
PO(O
Me)2
S61
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.2747.2607.2557.0297.0086.445
4.1864.1694.1514.133
2.4952.4842.4792.4702.4622.4572.4461.8521.8401.8301.8191.8081.5781.5661.5551.5431.5311.5061.2921.2741.256
2.132.03
0.88
2.02
1.00
0.97
4.0310.03
CO
2 Et
BocHN
S62
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.442
152.699
136.773134.637
126.790
118.634
80.48177.31877.00076.682
60.654
28.321
25.70123.932
16.81014.251
CO
2 Et
BocHN
S63
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.0
7.260
6.9186.8966.6196.598
4.1834.1654.1484.1303.6062.4582.4482.4422.4352.4312.4252.4192.4081.8101.8001.7971.7891.7871.7791.7761.7661.5411.5301.5281.5181.5171.5071.5051.494
1.2911.2731.2551.2511.2401.2351.2301 2241 2191 2141 203
1.99
2.00
2.01
1.87
0.98
0.97
1.04
3.05 1.11
CD
Cl3, 400 M
Hz
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
1.8101.8001.7971.7891.7871.7791.7761.766
1.5411.5301.5281.5181.5171.5071.5051.494
1.291
1.273
1.2551.2511.2401.2351.2301.2241.2191.2141.203
CO
2 Et
H2 N
S64
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
173.698
144.902
129.836127.223
115.122
77.31877.00076.682
60.537
25.80723.719
16.58014.247
CO
2 Et
H2 N
S65
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.3527.3277.2997.2887.2607.1267.1027.0777.0217.0066.9776.9316.9036.8776.5496.521
4.2904.1904.1664.1434.1194.0252.4612.4472.4392.4302.4262.4172.4082.3951.8091.7951.7921.7811.7781.7671.7641.7501.5451.5301.5141.4991.4821.2951.2711.2561.2471.2411.2341.2281.2191.213
2.03
2.96
8.04
0.87
1.982.10
1.00
1.00
1.06
4.10
CD
Cl3, 300 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.801.90
2.00
1.8091.7951.7921.7811.7781.7671.7641.750
1.5451.5301.5141.4991.482
1.2951.2711.2561.2471.2411.2341.2281.2191.2131.2061.192
CO
2 Et
NHPhO
S66
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.754
157.541156.975
146.566
141.551
129.896129.725128.888127.224
123.284
122.032118.900
117.668117.440112.926
77.42577.00176.578
60.536
48.082
25.86023.744
16.56314.276
CO
2 Et
NHPhO
S67
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.3487.3307.3087.2927.2727.2607.1257.1067.0857.0197.0056.9856.9406.9186.8936.8886.5556.533
4.2942.5462.5362.5292.5222.5202.5132.5062.4961.8041.7911.7821.7731.7601.6071.5951.5831.5721.5601.3511.3401.3341.3231.3191.3141.303
2.00
2.922.063.02
3.02
1.99
0.96
0.981.021.05
CO
OH
NHPhO
S68
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
179.692
157.568156.982
146.715
141.491
129.909129.727
128.318127.372123.299122.043118.914117.681117.467112.981
77.31877.00076.683
48.090
26.87023.557
17.032
CO
OH
NHPhO
S69
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.2777.2607.2487.0497.020
6.475
3.1112.9832.4522.4382.4312.4222.4172.4082.4012.3871.9411.9271.9231.9131.9091.8991.8961.8821.6331.6191.6151.6021.5891.5851.5711.5041.2551.2491.2351.2281.2221 2141 187
2.003.57
0.90
3.013.01
1.02
0.98
1.00
1.00
9.02
CD
Cl3, 300 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50
2.60
2.4522.4382.4312.4222.4172.4082.4012.387
1.9411.9271.9231.9131.9091.8991.8961.882
1.6331.6191.6151.6021.5891.5851.5711.504
1.2551.2491.2351.2281.2221.2141.2071.2011.187
NHO
N
O
O
S70
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
173.442
152.699
136.773134.637
126.790
118.634
80.48177.31877.00076.682
60.654
28.320
25.70123.932
16.810
14.251
NHO
N
O
O
S71
CD
Cl3, 300 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.0
7.260
6.9426.9146.6296.601
3.584
3.1212.9822.4172.4032.3962.3862.3822.3732.3662.3521.9051.8881.8781.8741.8611.8461.5891.5751.5721.5581.5451.5421.5281.2091.1951.1881.1821.1741.1681 1611 14
2.01
2.04
1.95
3.053.05
1.04
1.02
1.02
1.06
CD
Cl3, 100 M
Hz
0.901.00
1.101.20
1.301.40
1.501.60
1.701.80
1.902.00
2.102.20
2.302.40
2.502.60
2.4172.4032.3962.3862.3822.3732.366
2.352
1.9051.8881.8781.8741.861
1.846
1.5891.5751.5721.5581.5451.5421.528
1.2091.1951.1881.1821.1741.1681.1611.147
H2 N
N
O
S72
CD
Cl3, 75 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
172.249
144.697
130.935127.161
115.195
77.42377.00076.576
37.28935.829
25.07022.730
15.682
H2 N
N
O
S73
CD
Cl3, 400 M
Hz
0.01.0
2.03.0
4.05.0
6.07.0
8.09.0
10.011.0
12.013.0
7.3447.3247.3067.2887.2697.2607.1377.1187.1027.0867.0247.0006.9806.9526.9316.9016.8866.8816.5546.5334.2894.0573.1182.9842.4072.3922.3832.3752.3712.3591.8951.8831.8721.8631.8511.5831.5711.5601.5481.5371.2011.1901.1851.1811.1751.1711.1651.154
3.031.996.03
2.00
2.010.76
2.983.01
1.01
1.01
1.00
1.01
CD
Cl3, 400 M
Hz
1.001.10
1.201.30
1.401.50
1.601.70
1.801.90
2.002.10
2.202.30
2.402.50 2.407
2.3922.3832.3752.3712.359
1.8951.8831.8721.8631.851
1.5831.5711.5601.5481.537
1.2011.1901.1851.1811.1751.1711.1651.154
1.01
1.01
1.00
1.01
NH
N
O
PhO
S74
CD
Cl3, 100 M
Hz
010
2030
4050
6070
8090
100110
120130
140150
160170
180190
200210
220230
172.279
157.508156.967
146.367
141.585
129.903129.872129.711127.131123.267122.057118.864117.694117.422112.945
77.31877.00076.682
48.132
37.28535.814
25.09322.685
15.638
NH
N
O
PhO
S75